The proposed research project is designed to examine the pathogenesis of severe malarial anemia in Thailand to define those elements that are attributable to infection with Plasmodium falciparum. Anemia is an inevitable consequence of malarial infection. Severe anemia [here defined as a hemoglobin concentration (Hb) < 7.0 g/dL] is a major complication in all endemic regions. The pathological basis for severe malarial anemia is complex, multifaceted and poorly understood, involving both increased destruction and decreased production of red blood cells. Moreover, susceptibility to the development of anemia is influenced by acquired and genetic host features as well as by plasmodial factors. The proposed research continues an established, long- term cooperative effort between investigators at Mahidol, Howard and Columbia Universities. This multidisciplinary collaborative project will assess the relative contributions of accelerated destruction and impaired production of erythrocytes in the pathogenesis of the severe anemia of falciparum malaria, using biotinylated red cell survival studies, automated reticulocyte counts, determinations of transferrin receptor, phenotypic and genotypic studies of malarial susceptibility, and measurements of pro- (Th-l) and anti- (Th-2) inflammatory cytokines. This prospective study of adults admitted to the Hospital for Tropical Disease has two specific aims: (I) to test the hypothesis that severe anemia on admission with acute falciparum malaria is the result of accelerated clearance of parasitized and non-parasitized red blood cells combined with cytokine-mediated suppression of erythropoiesis; and (2) to test the hypothesis that persistent severe anemia after successful treatment of acute falciparum malaria is the consequence of dyserythropoiesis and ineffective erythropoiesis, determined by an immunoregulatory imbalance in pro- (Th-1) and anti- (Th-2) inflammatory responses. The results of the proposed research will provide new information about the pathogenesis of anemia with falciparum malaria that can be used to develop innovative prevention and treatment strategies and ultimately lead to improved control of malarial infection.